Genome-wide association studies (GWAS) have identified replicated associations with COPD susceptibility, including the chromosome 15 locus {CHRNA3/5, IREB2), HHIP, and FAM13A. Multiple studies have also examined genome-wide gene expression profiles in patients with COPD. Gene expression profiling can identify novel COPD genes and help define the pathways by which these GWAS-discovered genes affect COPD. Preliminary data from biological and functional validation studies suggests that IREB2, one such gene identified through gene expression profiling and GWAS in human COPD, may influence COPD through effects on autophagy. This approach has pointed to a novel pathway in COPD, namely autophagy. Autophagy has been shown to play a role in common diseases, and our group has demonstrated the potential relevance of autophagy and apoptosis in emphysema. In this project, we will test two hypotheses: (1) Gene expression profiling in human COPD lung tissue and mouse models will identify novel genes for COPD and genes whose expression is correlated with IREB2, HHIP, and FAM13A, in order to elucidate the pathways of these genes'actions in COPD. (2) IREB2, a COPD susceptibility gene identified through gene expression profiling and GWAS, when induced by cigarette smoke regulates the autophagic process, which facilitates downstream apoptosis promoting the development of emphysema. We will address the following Specific Aims: (1) Human Gene Expression Profiling: We will perform micro-array gene expression profiling in human lung tissue samples to identify genes that are differentially expressed between COPD cases and controls. Gene expression will be validated in airway epithelial cells and alveolar macrophages from former smokers with and without COPD to determine tissue specificity of gene expression. (2) Gene Expression in Murine Models: We will perform micro-array gene expression profiling in lung tissue in 2 wild-type strains with differing susceptibility to cigarette smoke-induced emphysema and in 3 knock-out mouse models { Ireb2-/-, Hhip-/- ,Fam13a-/-) before and after cigarette smoke exposure and in a cell model of airway epithelial cells cultured at an air-liquid interface to identify genes involved in COPD development in these animals. (3) Ireb2-/- and autophagy: We will determine the functional role of Ireb2 in susceptibility to experimental cigarette smoke-induced emphysema. At the conclusion of this project, we will have identified novel genes for COPD and improved our understanding of the roles of HHIP, FAM13A, and IREB2 in COPD, with specific attention to the effects on autophagy and apoptosis pathways. The assessment of human and murine gene expression in this project will complement the genetics and epigenetics methods in Projects 1 and 3, respectively. Integration of these datasets will expand our knowledge of the functional genomics of COPD.